The present application claims priority to Korean Patent Application No. 10-2015-0099994, filed on Jul. 14, 2015, the entire contents of which are incorporated herein by reference.
Aminoacyl-tRNA synthetase is an enzyme that attaches a specific amino acid precisely to its cognate tRNA and it plays an essential role in protein synthesis. The process of attaching amino acids to respective cognate tRNAs is divided into two stages: The first step is to activate the amino acid to aminoacyl adenylate by consuming one ATP, while the second step is to transfer the activated amino acid to the tRNA. Aminoacyl-tRNA synthetases of mammals have similar roles as those of prokaryotes, but have additional domains. These additional domains have been known to be involved in the formation of various complexes with other aminoacyl-tRNA synthetases or other regulatory factors. It has recently been shown that this structural complexity is related to the functional diversity of aminoacyl-tRNA synthetases and to various human diseases.
Chemokines, on the other hand, play an indispensable role in attracting white blood cells to various tissues of the body as leukocyte chemotactic factors. The process is essential for physical responses to both inflammation and infection. Chemokines and their receptors are central to the pathophysiology of immunomodulatory, inflammatory and infectious diseases. Especially, it has been shown that interaction of specific chemokines with their receptors could elicit certain pathological consequences, including autoimmune diseases. Therapeutic approaches for modulating the activity of chemokines or their receptors have been proposed.
The CC chemokine receptor 3 (CCR3) is a GPCR (G protein-coupled receptor) for chemokines including eotaxin-1, eotaxin-2, RANTES, MCP-2, MCP-3 and MCP-4. CCR3 causes an eosinophilic leukocyte reaction in peripheral blood and airways. CCR3 is expressed not only on the surface of eosinophilic leukocytes but also on that of basophilic leukocytes, mast cells and type 2 helper T lymphocytes. CCR3 mRNA and protein levels are elevated in bronchial mucosa of asthmatic patients in relation to airway hyper-responsiveness. The fact that CCR3 participates in airway infiltration of eosinophilic leukocytes has been demonstrated in CCR3-deficient mice studies. The human CCR3 gene (MIM #601268) is located on chromosome 3p21.3 associated with atopic dermatitis and asthma. Thus, the binding of chemokine ligands to CCR3 is known to be an important regulator of inflammatory and immunomodulatory conditions, including autoimmune diseases such as asthma, rhinitis and allergic diseases and rheumatoid arthritis. Graves' disease and arteriosclerosis, and a variety of pathological contributions of CCR3 have been found, including the ability to detect choroidal neovascularization through a ligand that binds to CCR3, as described in U.S. Pat. No. 8,778,616B2.
In the past, antagonists to a receptor were screened to treat the corresponding receptor-mediated diseases in regard to the ligands and receptors involved in specific pathological phenomena. However, in the case of substantially blocking only the action of the receptor indiscriminately, the adverse effect is caused by the pathologic entry of the lesion into the adaptation state (i.e., other receptors regulate pathology) or excessive suppression of the favorable function of the receptor. The inhibition of the action of the ligand causing the disease on the receptor is also considered to be important in the prevention and treatment of diseases.